The long-term objective of this proposal is to understand how the activity of stem cells is properly regulated to maintain homeostasis and tissue integrity. The hair follicle, one of the important skin appendages, is an ideal paradigm to address this problem. Hair follicles undergo cycles of growth (anagen), destruction (catagen) and rest (telogen) phases. Hair follicle stem cells (HFSCs) are located in a permanent protrusion of the hair follicle, a structure known as the bulge. HFSCs in the bulge cycle infrequently. During normal homeostasis, HFSCs only proliferate in a very transient window of anagen, while remaining quiescent during all the other phases. HFSCs can also become activated upon wounding. Dis-regulation of HFSC activity results in severe consequences. For example, alopecia (hair loss) and delayed wound healing may arise from inefficient activation of HFSCs. On the contrary, skin tumors, such as basal cell carcinoma and squamous cell carcinoma, can derive from HFSC hyper-proliferation. Stem cell activity is heavily influenced by their microenvironment, known as the niche. Traditionally, studies about niche focus only on the surrounding heterologous cell types, i.e., cells originated from a different lineage. Recent studies including my own discover the importance of stem cell progeny as niche components in several vertebrate and invertebrate stem cell systems, which is previously unrecognized. In the hair follicle, my preliminary studies have identified two important progeny populations as critical regulators for HFSC proliferation. The central hypothesis to be tested by this proposal is that feedback regulation from HFSC progeny is crucial for the proper behavior and activity of HFSCs. This hypothesis will be tested in this grant application by experiments that: 1) examine candidate signals expressed by the progeny 2) determine the contributions of the progeny to HFSC activation under physiological and pathological conditions and 3) identify novel functional factors expressed by the progeny to regulate HFSCs. Candidate signals will be investigated during the mentored phase. The contributions of progeny under dynamic conditions as well as identified novel factors expressed by the progeny will be follow-up during the independent phase. Successful completion of the proposed experiments will significantly advance our understanding of the cell types and signals that regulate HFSC proliferation and quiescence. In addition, these proposed studies will potentially lead to the development of therapeutic treatments for skin disorders associate with aberrant stem cell activity. My long-term career goal is to lead a successful, independent, and well-funded laboratory studying skin and stem cell biology. My graduate and postdoctoral training up to date has prepared me technically and intellectually to develop rigorous research projects. This career development award and my proposed research plan will further provide me with opportunities to expand my knowledge in skin stem cell biology and mouse genetics, gain new skills in bioinformatics analysis, mouse embryo manipulation, image-based FACS analysis, and further accumulate experience to improve mentoring, presentation, and writing skills, all of which are critical to my fuure success as an independent researcher. The reagents generated during the mentored phase will also help to build up my research program in the independent phase. The Rockefeller University together with its two neighboring institutions, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, offer a prime research environment and many workshops and courses to support my proposed research and my career development. I will have constant interactions with my mentor Dr. Elaine Fuchs, my collaborator Dr. Olivier Elemento, and the skin and mouse developmental biology communities in the New York area. Together they will assess my progress and provide critique or advice. In summary, the proposed studies and career development plan will better prepare me for my independent scientific career, ensure that I achieve my long-term career goals, and allow me to make continuous contributions towards our understanding of how stem cell activity is regulated in homeostasis and disease.